1. Field of the Invention
This invention concerns the systemic administration of an inhibitor of fatty acid synthase (E.C. 2.3.1.85, FAS) by any suitable route to achieve weight loss and/or reduction of adipocyte mass without significant toxicity. Use of FAS inhibitors for this purpose is not restricted to humans or any species, but includes reduction of adipocyte mass in livestock and poultry. This invention also concerns the synthesis of a family of compounds (.alpha.-methylene-.beta.-carboxy-.gamma.-butyrolactones) which are fatty acid synthesis inhibitors, and the use of these compounds to achieve weight loss, to treat susceptible cancer cells, or in other applications characteristic of FAS inhibitors.
2. Review of Related Art
Compounds and proteins which induce reduction of weight or adipocyte mass in mammals may act through the following mechanisms: [1] increased fat mobilization, such as human chorionic gonadotrophin (HCG) induced metabolism of fat stores (Bray, et al., "Nutritional Support of Medical Practice," Harper and Row, Philadelphia, 1983); [2] increased calorigenesis, such as that induced by thyroid hormone (Abraham et al., 1985, Int. J. Obes., 9:433-42); [3] decreased appetite, induced by anorexic agents such as felbamate and dexfenfluramine (McTavish et al., 1992, Drugs, 43:713-33); [4] decreased lipogenesis (see Table 1 below); and [5] mutated or decreased blood levels of the ob gene product (Halaas et al., 1995, Science, 269:543-546). In mice (Kannan et al., 1980, Lipids, 15:993-8) and man, significant fatty acid synthesis occurs in liver (Triscari et al., 1985, Metabolism, 34:580-7; Barakat et al., 1991, Metabolism, 40:280-5) and adipose tissue (Goldrick et al., 1974, Clin. Sci. Mol. Med., 46:469-79), and rates of fatty acid synthesis are higher in obese mice or humans (Angel et al., 1979, Eur. J. Clin. Invest., 9:355-62; Belfiore et al., 1976, Metabolism, 25:483-93). Hence, it is not surprising that a number of weight reducing agents reduce de novo fatty acid synthesis. Table 1 provides a list of agents known to both inhibit lipogenesis and induce weight loss.
TABLE 1 ______________________________________ Compounds Which Induce Weight Loss ENZYME TARGET and REFERENCES and COMPOUND TYPE OF INHIBITION SPECIES STUDIED ______________________________________ TPIA & CPIB acetyl-CoA carboxylase, Maragoudakis, 1969, mixed competitive and J. Biol. Chem, 244: (non-competitive) 5005-13 (rodent study) Sodium 2-n-penta- acetyl-CoA carboxylase, Whittington et al., decylbenzimidazole-5- (competitive (?)) 1987, Int. J. Obes., 11: carboxylate 619-29 (rodent study) Dehydroepiando- glucose-6-phosphate Yen et al., 1981, sterone dehydrogenase, Lipids, 12: 409-13 (competitive) (rodent study) (-) hydroxycitrate ATP citrate lyase, Greenwood et al., (competitive) 1981, Am. J. Physiol., 240: E72-8. (rodent study) 30 kD protein enzyme target unknown, Harris, et al., 1989, inhibits FA synthesis Am. J. Physiol., 257: R326-36 (rodent study) ob gene product protein produced by Halaas et al., 1995, adipocytes which inhibits Sciences, 269: 543-6 appetite (rodent study) ______________________________________ Interestingly, no inhibitors of fatty acid synthase (FAS) (E.C. 2.3.1.85) are mentioned in prior art as agents which produce weight loss.